The Carbon Dioxide Tension and Acid-Base Balance of Jejunal Secretions in Man

McGee, Lemuel C.; Hastings, A. Baird

doi:10.1016/s0021-9258(18)45087-9

Cited by 48 publications

(18 citation statements)

References 15 publications

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“…In healthy subjects, bicarbonate concentrations in duodenum and jejunum are 6.7 and 8.2 mM, respectively [22,23]. Nevertheless, they may vary in jejunum between 2-10 and 6-20 mM, as well [24]. Luminal bicarbonate contributes to small intestinal buffer capacities between 3.2 and 5.6 mmol/L/∆pH [8,25], although values as high as 13 mmol/L/∆pH have also been reported [26].…”

Section: Gastrointestinal Physiology: "Bypassing the Upper Gastrointe...mentioning

confidence: 99%

In Vitro Methodologies for Evaluating Colon-Targeted Pharmaceutical Products and Industry Perspectives for Their Applications

et al. 2022

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Several locally acting colon-targeted products to treat colonic diseases have been recently developed and marketed, taking advantage of gastrointestinal physiology to target delivery. Main mechanisms involve pH-dependent, time-controlled and/or enzymatic-triggered release. With site of action located before systemic circulation and troublesome colonic sampling, there is room for the introduction of meaningful in vitro methods for development, quality control (QC) and regulatory applications of these formulations. A one-size-fits-all method seems unrealistic, as the selection of experimental conditions should resemble the physiological features exploited to trigger the release. This article reviews the state of the art for bio-predictive dissolution testing of colon-targeted products. Compendial methods overlook physiological aspects, such as buffer molarity and fluid composition. These are critical for pH-dependent products and time-controlled systems containing ionizable drugs. Moreover, meaningful methods for enzymatic-triggered products including either bacteria or enzymes are completely ignored by pharmacopeias. Bio-predictive testing may accelerate the development of successful products, although this may require complex methodologies. However, for high-throughput routine testing (e.g., QC), simplified methods can be used where balance is struck between simplicity, robustness and transferability on one side and bio-predictivity on the other. Ultimately, bio-predictive methods can occupy a special niche in terms of supplementing plasma concentration data for regulatory approval.

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Section: Gastrointestinal Physiology: "Bypassing the Upper Gastrointe...mentioning

confidence: 99%

In Vitro Methodologies for Evaluating Colon-Targeted Pharmaceutical Products and Industry Perspectives for Their Applications

et al. 2022

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“…(11)(12)(13)(14) Using the pCO 2 /pH method, the bicarbonate concentration in the upper intestine (duodenum and jejunum) of fasted adults has been measured to range between 2 and 20 mM, and the influx of hydrochloric acid into the upper small intestine has been shown to result in a significant increase in bicarbonate secretion rates. (6,(15)(16)(17)(18) Here it should be mentioned that pCO 2 /pH measurements have been criticized as sometimes leading to an underestimation of bicarbonate concentration, (19) in which case values at the upper end of the reported ranges for the stomach and upper intestine are likely to be closer to the true intraluminal values.…”

Section: Introductionmentioning

confidence: 97%

Measuring pH and Buffer Capacity in Fluids Aspirated from the Fasted Upper Gastrointestinal Tract of Healthy Adults

et al. 2020

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Purpose: The design of biorelevant conditions for in vitro evaluation of orally administered drug products is contingent on obtaining accurate values for physiologically relevant parameters such as pH, buffer capacity and bile salt concentrations in upper gastrointestinal fluids. Methods:The impact of sample handling on the measurement of pH and buffer capacity of aspirates from the upper gastrointestinal tract was evaluated, with a focus on centrifugation and freeze-thaw cycling as factors that can influence results. Since bicarbonate is a key buffer system in the fasted state and is used to represent conditions in the upper intestine in vitro, variations on sample handling were also investigated for bicarbonate-based buffers prepared in the laboratory.Results: Centrifugation and freezing significantly increase pH and decrease buffer capacity in samples obtained by aspiration from the upper gastrointestinal tract in the fasted state and in bicarbonate buffers prepared in vitro. Comparison of data suggested that the buffer system in the small intestine does not derive exclusively from bicarbonates.Conclusions: Measurement of both pH and buffer capacity immediately after aspiration are strongly recommended as "best practice" and should be adopted as the standard procedure for measuring pH and buffer capacity in aspirates from the gastrointestinal tract. Only data obtained in this way provide a valid basis for setting the physiological parameters in physiologically based pharmacokinetic models.

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“…Bicarbonate is the primary buffering system in the human GI tract. The bicarbonate concentrations in a fasted stomach range from 7 to 20 mequiv/L, , about 2–30 mM in the duodenum and jejunum and ∼30–75 mM in the ileum. − In a recent study, the pH and buffer capacity of human GI fluids aspirated from the stomach, duodenum, proximal jejunum, and mid/distal jejunum of 37 healthy human subjects were determined in both fed and fasted conditions . These studies highlight the low buffer capacity along the human GI tract, which is on average 2.26 (μmol/(mL·ΔpH)) in the fasted state and 2.66 (μmol/(mL·ΔpH)) in the fed state.…”

Section: Introductionmentioning

confidence: 99%

Hierarchical Mass Transfer Analysis of Drug Particle Dissolution, Highlighting the Hydrodynamics, pH, Particle Size, and Buffer Effects for the Dissolution of Ionizable and Nonionizable Drugs in a Compendial Dissolution Vessel

et al. 2020

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Dissolution is a crucial process for the oral delivery of drug products. Before being absorbed through epithelial cell membranes to reach the systemic circulation, drugs must first dissolve in the human gastrointestinal (GI) tract. In vivo and in vitro dissolutions are complex because of their dependency upon the drug physicochemical properties, drug product, and GI physiological properties. However, an understanding of this process is critical for the development of robust drug products. To enhance our understanding of in vivo and in vitro dissolutions, a hierarchical mass transfer (HMT) model was developed that considers the drug properties, GI fluid properties, and fluid hydrodynamics. The key drug properties include intrinsic solubility, acid/base character, pK a, particle size, and particle polydispersity. The GI fluid properties include bulk pH, buffer species concentration, fluid shear rate, and fluid convection. To corroborate the model, in vitro dissolution experiments were conducted in the United States Pharmacopeia (USP) 2 dissolution apparatus. A weakly acidic (ibuprofen), a weakly basic (haloperidol), and a nonionizable (felodipine) drug were used to study the effects of the acid/base character, pK a, and intrinsic solubility on dissolution. 900 mL of 5 mM bicarbonate and phosphate buffers at pH 6.5 and 37 °C was used to study the impact of the buffer species on drug dissolution. To investigate the impacts of fluid shear rate and convection, the apparatus was operated at different impeller rotational speeds. Moreover, presieved ibuprofen particles with different average diameters were used to investigate the effect of particle size on drug dissolution. In vitro experiments demonstrate that the dissolution rates of both the ionizable compounds used in this study were slower in bicarbonate buffer than in phosphate buffer, with the same buffer concentration, because of the lower interfacial buffer capacity, a unique behavior of bicarbonate buffer. Therefore, using surrogates (i.e., 50 mM phosphate) for bicarbonate buffer for biorelevant in vitro dissolution testing may overestimate the in vivo dissolution rate for ionizable drugs. Model simulations demonstrated that, assuming a monodisperse particle size when modeling, dissolution may overestimate the dissolution rate for polydisperse particle size distributions. The hydrodynamic parameters (maximum shear rate and fluid velocity) under in vitro conditions in the USP 2 apparatus under different rotational speeds are orders of magnitude higher compared to the in vivo situation. The inconsistencies between the in vivo and in vitro drug dissolution hydrodynamic conditions may cause an overestimation of the dissolution rate under in vitro conditions. The in vitro dissolution data supported the accuracy of the HMT for drug dissolution. This is the first drug dissolution model that incorporates the effect of the bulk pH and buffer concentration on the interfacial drug particle solubility of ionizable compounds, combined with the medium hydrodynamics effect (di...

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The Carbon Dioxide Tension and Acid-Base Balance of Jejunal Secretions in Man

Cited by 48 publications

References 15 publications

In Vitro Methodologies for Evaluating Colon-Targeted Pharmaceutical Products and Industry Perspectives for Their Applications

In Vitro Methodologies for Evaluating Colon-Targeted Pharmaceutical Products and Industry Perspectives for Their Applications

Measuring pH and Buffer Capacity in Fluids Aspirated from the Fasted Upper Gastrointestinal Tract of Healthy Adults

Hierarchical Mass Transfer Analysis of Drug Particle Dissolution, Highlighting the Hydrodynamics, pH, Particle Size, and Buffer Effects for the Dissolution of Ionizable and Nonionizable Drugs in a Compendial Dissolution Vessel

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